Patent GB-870384-A (GB)
Title: 3-carboxy-4-methyl-naphthalene derivatives and a process for preparing them
IPC: C07C65/24
Filed: 1958-06-09
Abstract: The invention comprises 8-methoxy-5-chloro-4-methyl-3-carboxy-hydroxynaphthalene.  This compound may be obtained by condensing m-methoxy-acetophenone with a succinic ester, catalytically hydrogenating the cinnamic acid derivative so obtained at the ethylenic bond, introducing a chlorine atom in the para-position to the methoxy group, then effecting ring closure at raised temperature in the presence of a condensing agent, dehydrogenating the tetralone derivative which has been formed to the corresponding naphthalene compound and hydrolysing the ester group. Derivatives of this compound may be obtained by processes of demethylation, alkylation, or acylation. Thus, the hydroxyl group in 1-position may be acylated, or both the hydroxyl group and the carboxyl group may be alkylated, or the methoxy group may be demethylated.  The m-methoxy-acetophenone may be condensed in the presence of an alkali metal alcoholate, amide, or hydride, e.g. sodium hydride, with a succinic ester such as the dimethyl or diethyl ester.  A solvent such as benzene, toluene, or xylene, may be present.  Two isomeric compounds are formed; crystalline cis-meta-methoxy-a -carboxymethyl-b -methyl-cinnamic acid ethyl ester can be separated from the reaction products by filtration, whereas the trans isomer is an oily product.  The two isomers are hydrogenated catalytically at room temperature or elevated temperature and under atmospheric or elevated hydrogen pressure. Methanol or other aliphatic alcohol containing up to 4 carbon atoms in the molecule may be used as solvent.  Two disastereoisomeric g -(m-methoxyphenyl)-b -carbethoxy valeric acids are formed.  The subsequent chlorination may be effected with chlorine in presence of a solvent at low temperature e.g. -20 DEG C. to -5 DEG C.  Methylene chloride or chloroform may be used as solvent.  The chlorinated products, whose isolation is not necessary are submitted to ring-closure treatment e.g. heating to a temperature of 60-90 DEG C. in presence of a condensing agent such as sulphuric acid, boron trifluoride, anhydrous hydrofluoric acid, or polyphosphoric acid, and are thereby transformed into the cis-trans-isomeric 8-methoxy-5-chloro-4-methyl-3-carbethoxy-tetralones, one of the pure cis- or transisomeric tetralones being formed by each of the two diastereo-isomeric g -(m-methoxyphenyl)-b -carbethoxy valeric acids. The dehydrogenation of the isomeric tetralone derivatives leads in both cases to the same 8-methoxy-5-chloro -4-methyl-3-carboxy -1-hydroxynaphthalene.  This may be effected by bromination of the tetralone compound, preferably with exposure to light, subsequent splitting off of hydrogen bromide, and hydrolysis.  The 8-methoxy- 5-chloro- 4-methyl- 3-carboxy- 1-hydroxy-napthalene may be transformed into the corresponding 1,8-dihydroxy compound known as chloro-terranaptholic acid, by melting it with pyridinium chloride. It may be converted into 1,8-dimethoxy-5-chloro-4-methyl-3-carbomethoxy-naphthalene by methylation with methyl iodide or dimethyl sulphate.  It may be acetylated with acetic anhydride in the presence of a base such as pyridine to yield 8-methoxy-5-chloro-4-methyl-3-carboxy-1-acetoxy-naphthalene. Reference is made to the production of 4-acetoxy-7-methoxy-1-methyl-2-carboethoxy-naphthalene by the action of sodium acetate, acetic acid, and acetic anhydride on the trans-m-methoxy-a -carboxymethyl-b -methyl-cinnamic acid ethyl ester. Specification 768,760 is referred to.